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WASHINGTON, DC March 26, 2008 â€“ A new study released today confirms that the widely used botulinum neurotoxin type A (sold commercially under the brand names BOTOX®, Dysport®, Neuronox®, Xeomin®, and VISTABEL®) can move from the original injection site into the central nervous system, and identifies for the first time the biological mechanism by which it may do so. The results, published April 2 in The Journal of Neuroscience, are based on animal research and build on earlier reports about the possible migration of botulinum neurotoxin, used both in cosmetic treatments and in therapies for neuromuscular disorders. The substance can disrupt nerve cell activity in the central nervous system, creating potential clinical implications that further research may inform.

Botulinum neurotoxin was generally thought to act locally,says Christopher von Bartheld, MD, at the University of Nevada School of Medicine, who was not affiliated with the study. But these basic research findings show how it can be transported and spread along axons to distant sites in the central nervous system of animals, where it can have significant and long-lasting effects on neuronal function.

Botulinum neurotoxin disrupts cell communication by destroying a protein essential to signaling between nerve cells. Matteo Caleo, PhD, of Italy's National Research Council, and colleagues confirmed the movement of botulinum neurotoxin A by detecting the remnants of proteins it had fragmented. This evidence helped show that nerve cells at the injection site absorbed some of the botulinum neurotoxin, which was then transported across the cell and released to connected cells, where the proteins also were destroyed. The direction it traveled was opposite to that of the nerve cells electrical signals. These findings contradict previous research, which suggested that botulinum neurotoxin was completely degraded at the injection site and not transported beyond it.

Caleos team traced the movement of botulinum neurotoxins in mice and rats. The team made injections into the whisker muscles, the hippocampus, and the superior colliculus, a brain region that receives input from the eye. Using protein analysis and microscopic examination of the rodents brain tissue, the researchers found that, within three days, active forms of botulinum neurotoxin had migrated from the whisker muscles to the brain stem, from one hippocampus to the hippocampus on the opposite side of the brain, and from the superior colliculus back to the eye.

Brain cell activity was disrupted both where botulinum neurotoxin was injected and in some of these distant but connected sites. Caleo and his colleagues noted in particular that the effects of the botulinum neurotoxin injection on the hippocampus were still present six months later.

These studies suggest that toxin concentration and dosage at the injection site are key factors influencing this transport, says David Sherry, PhD, of the University of Oklahoma Health Sciences Center, also unaffiliated with the study. Side effects from botulinum neurotoxin could be prevented by blocking the toxin's transport into the tips of nerve cells or back across the nerve cells. One key avenue for further study is to more precisely characterize the mechanisms responsible for transporting the toxin out of the spaces between nerve cells, across the cells, and for transfer to other nerve cells.

The work was supported by grants from the Telethon Foundation and the Italy-based Investment Fund for Basic Research (FIRB).

The Journal of Neuroscience is published by the Society for Neuroscience, an organization of more than 38,000 basic scientists and clinicians who study the brain and nervous system. Caleo can be reached at
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